USRE41315E1 - Modulators of dopamine neurotransmission - Google Patents

Modulators of dopamine neurotransmission Download PDF

Info

Publication number
USRE41315E1
USRE41315E1 US11/904,013 US90401300A USRE41315E US RE41315 E1 USRE41315 E1 US RE41315E1 US 90401300 A US90401300 A US 90401300A US RE41315 E USRE41315 E US RE41315E
Authority
US
United States
Prior art keywords
phenyl
piperazine
propyl
compound
trifluoromethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US11/904,013
Other languages
English (en)
Inventor
Clas Sonesson
Bengt Andersson
Susanna Waters
Nicholas Waters
Joakim Tedroff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Saniona AB
Original Assignee
NSAB Filial af Neurosearch Sweden AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by NSAB Filial af Neurosearch Sweden AB filed Critical NSAB Filial af Neurosearch Sweden AB
Assigned to NEUROSEARCH SWEDEN AB reassignment NEUROSEARCH SWEDEN AB CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: A CARLSSON RESEARCH AB
Assigned to NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE reassignment NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NEUROSEARCH SWEDEN AB
Application granted granted Critical
Publication of USRE41315E1 publication Critical patent/USRE41315E1/en
Assigned to SANIONA AB reassignment SANIONA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to new modulators of dopamine neurotransmission, and more specifically to new substituted 4-(phenyl N-alkyl)-piperazines and 4-(phenyl N-alkyl)-piperidines, and use thereof.
  • Dopamine is a neurotransmitter in the brain. Since this discovery, made in the 1950s, the function of dopamine in the brain has been intensely explored. To date, it is well established that dopamine is essential in several aspects of brain function including motor, cognitive, sensory, emotional and autonomous (e.g. regulation of appetite, body temperature, sleep) functions. Thus, modulation of dopaminergic function may be beneficial in the treatment of a wide range of disorders affecting brain functions. In fact, both neurologic and psychiatric disorders are treated with medications based on interactions with dopamine systems and dopamine receptors in the brain.
  • Drugs that act, directly or indirectly, at central dopamine receptors are commonly used in the treatment of neurologic and psychiatric disorders, e.g. Parkinson's disease and schizophrenia.
  • dopaminergic pharmaceuticals have severe side effects, such as extrapyramidal side effects and tardive dyskinesia in dopaminergic antagonists used as antipsychotic agents, and dyskinesias and psychoses in dopaminergic agonists used as anti-Parkinson's agents.
  • Therapeutic effects are unsatisfactory in many respects.
  • novel dopamine receptor ligands with selectivity at specific dopamine receptor subtypes or regional selectivity are sought for.
  • dopamine receptor agonists i.e. dopamine receptor ligands with some but not full intrinsic activity at dopamine receptors, are being developed to achieve an optimal degree of stimulation at dopamine receptors, avoiding excessive dopamine receptor blockade or excessive stimulation.
  • the object of the present invention is to provide new pharmaceutically active compounds, especially useful in treatment of disorders in the central nervous system, which do not have the disadvantages of the above described substances.
  • the compounds of the present invention have unexpectedly been found to act preferentially on dopaminergic systems in the brain. They have effects on biochemical indices in the brain with the characteristic features of dopamine antagonists, e.g. producing increases in concentrations of dopamine metabolites.
  • the compounds of this invention surprisingly show a dopaminergic action profile with clear antagonist like effects on brain neurochemistry but no, or mild, antagonist like effects, on normal behavior, they can activate animals with a low baseline activity, but can also inhibit behavior in states of hyperactivity.
  • the action profile suggests modulatory effects on dopaminergic functions, clearly different from known compounds belonging to these chemical classes or effects anticipated of typical dopamine receptor antagonists or agonists from these or other chemical classes.
  • the novel class of dopaminergic modulators presented in this invention may prove superior to presently known dopaminergic compounds in the treatment of several disorders related to dysfunctions of the CNS, in terms of efficacy as well as side effects.
  • Some compounds of this invention have been found to have surprisingly good pharmacokinetic properties including high oral bioavailability. They are thus suitable for the preparation of orally administered pharmaceuticals. There is no guidance in the prior art how to obtain compounds with this effect on dopamine systems in the brain.
  • the present invention relates to new di-substituted 4-(phenyl-N-alkyl)-piperazines and di-substituted 4-(phenyl-N-alkyl)-piperidines in the form of free base or pharmaceutically acceptable salts thereof, process for their preparation, pharmaceutical compositions containing said therapeutically active compound and to the use of said active compound in therapy.
  • An objective of the invention is to provide a compound for therapeutic use, and more precisely a compound for modulation of dopaminergic systems in the mammalian brain including man. It is also an objective of the invention to provide a compound with therapeutic effects after oral administration.
  • the present invention is directed toward substituted 4-(phenyl N-alkyl)-piperazine or 4-(phenyl-N-alkyl)-piperidine compounds of Formula 1: wherein:
  • ADHD attention deficit hyper activity disorder
  • tic disorders such as Gilles de la Tourette's syndrome and other tic disorders.
  • speech disorders such as stuttering may improve. They may also be for regulating pathological disorders of food, coffee, tea, tobacco, alcohol and addictive drug intake and also to improve mental disorders associated with psychoactive substance overuse (including alcohol) including hallucinations, withdrawal symptoms, delusions, mood disorders, sexual and cognitive disturbances.
  • Anxiety disorders obsessive-compulsive disorder and other impulse control disorders, post traumatic stress syndrome, personality disorders, and conversion hysteria may also be treated with the compounds in the invention.
  • Other indications include sleep disorders, “jet lag” and disorders of sexual functions.
  • Neurological indications include the treatment of Huntington's disease, movement disorders such as dyskinesias including other choreas as well as primary, secondary and paroxysmal dystonias, tardive movement disorders such as tardive dyskinesia and tardive dystonia as well as other drug induced movement disorders.
  • Restless legs, periodic leg movements and narcolepsy may also be treated with compounds included in the invention. They may also improve mental and motor function in Parkinson's disease, and in related parkinsonian syndromes such as multiple system atrophies, progressive supranuclear palsy, diffuse Lewy body disorder and vascular parkinsonism. They may also be used to ameliorate tremor of different origins.
  • the compounds in the invention can also be used for the treatment of vascular headaches such as migraine and cluster headache, both as acute and prophylactic treatment. They may improve rehabilitation following vascular or traumatic brain injury. Moreover, they may be used to relieve pain in conditions characterized by increased muscle tone.
  • One preferred compound is 4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine, further illustrated in Example 9.
  • it has no significant inhibition on spontaneous behavior; 1287 ⁇ 272 cm/30 min (for controls) vs. 944 ⁇ 114 cm/30 min at 50 ⁇ mol/kg s.c.
  • it affect the locomotor activity of habituated rats from 1381 ⁇ 877 cm/60 min (for the controls) to 1300 ⁇ 761 cm/60 min at 50 ⁇ mol/kg s.c.
  • 4-(4-chloro-3-trifluoromethyl-phenyl)-1-propyl-piperidine has an oral availability (F) of 55% in rat.
  • 1-propyl-4-(3-trifluoromethyl-phenyl)-piperazine is not a substance according to the present invention.
  • 1-propyl-4-(3-trifluoromethyl-phenyl)-piperazine has an oral availability (F) of 9,5% in rat.
  • 1-(4-Chloro-3-nitro-phenyl)-4-propyl-piperazine shows the desired properties.
  • d-amphetamine induced hyperactivity is demonstrated by cis-4-(3,4-dichloro-phenyl)-2,6-dimethyl-1-propyl-piperazine, which is the compound of Example 35.
  • the compounds according to the invention are especially suitable for treatment of disorders in the central nervous system, and particularly for treatment of dopamine mediated disorders. They may, e.g. used to ameliorate symptoms of mood disorders, in obesitas as an anorectic agent and in other eating disorders, to improve cognitive functions and related emotional disturbances, to improve cognitive and motor dysfunctions associated with developmental disorders, to improve all symptoms of psychosis, including schizophrenia and schizophreniform disorders, to improve ongoing symptoms as well as to prevent vent the occurrence of new psychotic episodes, to regulate pathological disorders due to intake of food, coffee, tea, tobacco, alcohol and addictive drugs etc.
  • the compounds according to the invention can thus be used to treat symptoms in e.g.:
  • the synthesis of the present compounds is carried out by methods that are conventional for the synthesis of related known compounds.
  • the syntheses of compounds in Formula 1, in general, comprise the reaction of an intermediate that supplies the alkyl group with an intermediate piperidine or piperazine that supplies the amine group of Formula 2:
  • a convenient method of synthesis of the present compounds is by use of an alkyl iodide (e.g. 1-propyl-iodide).
  • alkyl iodide e.g. 1-propyl-iodide
  • other leaving groups besides iodide may be used on the alkyl group, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like.
  • the alkyl intermediate is reacted with the appropriate amine in the presence of any convenient acid scavenger.
  • the usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines.
  • Compounds of Formula 3: wherein X ⁇ N is accomplished by reacting compounds of Formula 4: with compounds of Formula 5: where Z is a leaving group like iodide.
  • Other leaving groups besides iodide may be used on the alkylgroup, of course, such as sulfonates, particularly methanesulfonate or toluenesulfonate, bromo and the like.
  • the alkyl intermediate is reacted with the appropriate amine in the presence of any convenient acid scavenger.
  • the usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and hydroxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines.
  • the reaction is performed in a suitable solvent such as n-butanol by heating at about 50-150° C.
  • the catalyst preferably Pd will have the ability to form ligand complex and undergo oxidative addition.
  • Typical Pd catalysts will be Pd 2 (dba) 3 (wherein dba refers to di-benzylidene acetone), Pd(PPh 3 ) 4 , Pd(OAc) 2 , or PdCl 2 [P (o-tol) 3 ] 2 and typical phosphine ligands will be BINAP, P(o-tol) 3 , dppf, or the like.
  • the usual bases such as alkali metal or alkaline earth metal carbonates, bicarbonates and alkyloxides are useful acid scavengers, as are some organic bases such as trialkylamines and trialkanolamines.
  • the reaction medium for such reactions may be any convenient organic solvents, which are inert to the basic conditions; acetonitrile, toluene, dioxane, NMP (N-methyl-2-pyrrolidone), DME (dimethoxyethane), DMF (N,N-dimethylformamide), DMSO (dimethylsulfoxide) and THF (tetrahydrofuran) solvents are useful.
  • organic solvents such as from ambient temperature to the reflux temperature of the reaction mixture, particularly from 50° C. to about 120° C.
  • the reaction may be carried out between compounds of Formula 8: wherein Y is, for example, a dialkylborane, dialkenylborane or boronic acid (e.g. BEt 2 , B(OH) 2 ) or a trialkyltin (e.g. SnMe 3 , SnBu3), and an aryl substituted with a leaving group of Formula 7: (for definition of Z, see above) in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according to known methods (Chem. Pharm. Bull., vol 33, 1985, 4755-4763, J. Am. Chem. Soc., vol. 109, 1987, 5478-5486., Tetrahedron Lett., vol.
  • Y is, for example, a dialkylborane, dialkenylborane or boronic acid (e.g. BEt 2 , B(OH) 2 ) or a trialkyltin (e.g. SnM
  • Y can also be a zink- or magnesium-halide group (e.g. ZnCl 2 , ZnBr 2 , ZnI 2 , MgBr, MgI) according to known methods (Tetrahedron Lett., vol. 33, 1992, 5373-5374, Tetrahedron Lett., vol. 37, 1996, 5491-5494 ).
  • ZnCl 2 , ZnBr 2 , ZnI 2 , MgBr, MgI zink- or magnesium-halide group
  • the catalyst preferably Pd will have the ability to form ligand complex and undergo oxidative addition.
  • the definition of ligands, bases and solvents, is mentioned above.
  • the transition metal catalyzed cross-coupling coupling reaction can be performed with the opposite substitution pattern: with an heteroaryl/alkenyl substituted with an leaving group of Formula 10: in the presence of a base and a zerovalent transition metal catalyst such as Pd or Ni, according known methods discussed in the previous paragraph.
  • Compounds of Formula 11 can be prepared by catalytic hydrogenation of the tetrahydropyridine or pyridine from the previous paragraph, using standard methods known in the art, generally with palladium on carbon, PtO 2 , or Raney nickel as the catalyst.
  • the reaction is performed in an inert solvent, such as ethanol or ethyl acetate, either with or without a protic acid, such as acetic acid or HCl.
  • an inert solvent such as ethanol or ethyl acetate
  • protic acid such as acetic acid or HCl.
  • arylhalides of Formula 7 wherein Z is Cl, Br, or I
  • alkyllithium reagents for example, butyllithium, sec-butyllithium or tert-butyl-lithium, preferably butyllitium or Mg (Grignard reaction) in an inert solvent.
  • Suitable solvents include, for example ether or tetrahydrofuran, preferably tetrahydrofuran. Reaction temperatures range from about ⁇ 110° C. to about 0° C.
  • the intermediate lithium anions or magnesium anions thus formed may then be further reacted with a suitable electrophile of Formula 12: wherein A is defined as a protecting group like t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl) or an alkylgroup like benzyl.
  • A is defined as a protecting group like t-Boc (tert-butoxycarbonyl), Fmoc (fluorenylmethoxycarbonyl), Cbz (benzyloxycarbonyl) or an alkylgroup like benzyl.
  • the intermediates of formula 13: which are formed require that the hydroky group be removed so as to result in compounds of Formula 1 (X ⁇ CH or C). This step may be accomplished by one of several standard methods known in the art.
  • a thiocarbonyl derivative for example a xanthate
  • a free radical process for example a free radical process, of which are known to those skilled in the art.
  • the hydroxyl group may be removed by reduction with a hydride source such as triethylsilane under acidic conditions, using such as, for example, trifluoroacetic acid or boron trifluoride.
  • the reduction reaction can be performed neat or in a solvent, such as methylene chloride.
  • a further alternative would be to first convert the hydroxyl group to a suitable leaving group, such as tosylate or chloride, using standard methods. The leaving group is then removed with a nucleophilic hydride, such as, for example, lithium aluminium hydride.
  • This last reaction is performed typically in an inert solvent, such as, ether or tetrahydrofuran.
  • Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol to an olefin with a reagent such as Burgess salt (J. Org. Chem., vol 38, 1973, 26) followed by catalytic hydrogenation of the double bond under standard conditions with a catalyst such as palladium on carbon.
  • the alcohol may also be dehydrated to the olefin by treatment with acid such as p-toluenesulfonic acid or trifluoroacetic acid.
  • the protecting group, A is removed under standard conditions known by those skilled in the art.
  • t-Boc cleavages are conveniently carried out with trifluoroacetic acid either neat or in combination with methylene chloride.
  • F-moc is conveniently cleaved off with simple bases such as, ammonia, piperidine, or morpholine, usually in polar solvents such as DMF and acetonitrile.
  • A is Cbz or benzyl
  • these are conveniently cleaved off under catalytic hydrogenation conditions.
  • the benzyl group can also be cleaved off under N-dealkylation conditions such as treatment with ⁇ -chloroethyl chloroformate (J. Org. Chem., vol 49, 1984, 2081-2082 ).
  • a radical R1 in a compound of the Formula 1 into another radical R1, e.g. by oxidizing methylsulfide to methylsulfone (for example by m-chloroperoxybenzoic acid), substitution of a triflate or halide group with a cyano group (for example palladium catalyzed cyanation), substitution of triflate or halide group with a ketone (for example palladium catalyzed Heck reaction with butyl vinyl ether), substitution of a triflate or halide group with a carboxamide (for example, palladium catalyzed carbonylation), or cleaving an ether by, for example, converting a methoxy group into the corresponding hydroxyl derivate, which can further be converted into the corresponding mesylate or triflate.
  • mesylate and triflate refers to OSO 2 CH 3 , CH 3 SO 3 or OSO 2 CF 3 , CF 3 SO
  • C 1 -C 4 alkyl refers to an alkyl containing 1-4 carbon atoms in any isomeric form.
  • the various carbon moieties are defined as follows:
  • Alkyl refers to an aliphatic hydrocarbon radical and includes branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl.
  • cycloalkyl refers to a radical of a saturated cyclic hydrocarbon such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • patient refers to an individual in need of the treatment and/or prevention according to the invention.
  • treatment used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition.
  • the treatment may either be performed in an acute or in a chronic way.
  • Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid addition salts of the compounds of this invention.
  • Illustrative acids are sulfuric, nitric, phosphoric, hydrochloric, citric, acetic, lactic, tartaric, palmoic, ethane disulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric, maleic, and benzoic acid.
  • These salts are readily prepared by methods known in the art.
  • the pharmaceutical composition containing a compound according to the invention may also comprise substances used to facilitate the production of the pharmaceutical preparation or the administration of the preparations.
  • substances are well known to people skilled in the art and may for example be pharmaceutically acceptable adjuvants, carriers and preservatives.
  • the compounds used according to the present invention will normally be administered orally, rectally, or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable non-toxic, acid addition salt, such as the hydrochloride, lactate, acetate, sulfamate salt, in association with a pharmaceutically acceptable carrier.
  • the carrier may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by a weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
  • the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidine, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • a concentrated sugar solution which may contain e.g.
  • the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compound.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, cornstarch or amylopectin), cellulose derivatives or gelatine.
  • liquids or semisolids of the drug can be filled into hard gelatine capsules.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.2% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain coloring agents, flavoring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a watersoluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from 0.5% to about 10% by weight. These solutions may also containing stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules. The use and administration to a patient to be treated in the clinic would be readily apparent to an ordinary skill in the art.
  • the present invention is also considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a cosequense of structural asymmetry in certain compounds of the instant series. Separation of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
  • an effective amount or a therapeutic amount of the compounds of the invention are from about 0.01 to about 500 mg/kg body weight daily, preferably 0.1-10 mg/kg body weight daily.
  • the compounds may be administered in any suitable way, such as orally or parenterally.
  • the daily dose will preferably be administered in individual dosages 1 to 4 times daily.
  • the animals were placed in separate motility meter boxes 50 ⁇ 50 ⁇ 50 cm equipped with an array of 16 ⁇ 16 photocells (Digiscan activity monitor, RXYZM (16) TAO, Omnitech Electronics, USA), connected to an Omnitech Digiscan analyzer and a Apple Macintosh computer equipped with a digital interface board (NB DIO-24, National Instruments, USA).
  • Behavioral data from each motility meter box, representing the position (center of gravity) of the animal at each time were recorded at a sampling frequency of 25 Hz and collected using a custom written LABViewTM application.
  • the data from each recording session were analyzed with respect to distance traveled and small-scale movements, e.g. stops in the center of the behavior recording arena, during the recording session.
  • velocity at each time point is calculated as the distance traveled since the preceding sample divided by the time elapsed since the preceding sample.
  • the number of stops is then calculated as the number of times that the velocity changes from a non-zero value to zero.
  • the number of stops in the center of the behavioral recording arena is calculated as the number of stops occurring at a position at least ten centimeters from the edges of the recording arena.
  • the rats were decapitated and their brains rapidly taken out and put on an ice-cold petri-dish.
  • the limbic forebrain, the striatum, the frontal cortex and the remaining hemispheral parts of each rat were dissected and frozen.
  • Each brain part was subsequently analyzed with respect to its content of monoamines and their metabolites.
  • the monoaminergic indices analyzed were dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA), and noradrenaline (NA).
  • test compounds of this invention were administered to the rat.
  • rats were implanted with one catheter in the jugular vein and one catheter in the carotid artery under ketamine anesthesia.
  • test compound is injected the either orally or in the jugular vein catheter.
  • Blood samples are collected during 8 hours from the arterial catheter.
  • the blood samples were heparinized and centrifuged.
  • Plasma is collected from the centrifuged samples and frozen. The levels of test compound were subsequently determined in each sample by means of gas chromatography mass spectrometry (Hewlett-Packard 5972MSD).
  • the plasma samples taken from the rats of the Sprague-Dawley strain, (0.5 ml) were diluted with water (0.5 ml), and 30 pmol (50 ⁇ l) of (( ⁇ )-S-3-(3-Ethylsulfonylphenyl)-N-n-propyl-piperidine as internal standard was added. The pH was adjusted to 11.0 by the addition of 25 ⁇ l saturated Na 2 CO 3 . After mixing, the samples were extracted with 4 ml dichloromethane by shaking for 20 min. The organic layer was, after centrifugation, transferred to a smaller tube and evaporated to dryness under a stream of nitrogen and subsequently redissolved in 40 ⁇ l toluene for GC-MS analysis.
  • a standard curve over the range of 1-500 pmol was prepared by adding appropriate amounts of test compound to blank plasma samples.
  • GC was performed on a HP-Ultra 2 capillary column (12 m ⁇ 0.2 mm ID), and 2 ⁇ l was injected in the splitless mode. The GC temperature was held at 90° C. for 1 minute following injection, and was then increased by 30° C./min to the final temperature of 290° C. Each sample was run in duplicate. The lowest detectable concentration of test compound was generally found to be 1 pmol/ml.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Gynecology & Obstetrics (AREA)
  • Addiction (AREA)
  • Child & Adolescent Psychology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Anesthesiology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Liquid Crystal Substances (AREA)
  • Control Of El Displays (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
  • Error Detection And Correction (AREA)
US11/904,013 1999-12-22 2000-12-22 Modulators of dopamine neurotransmission Expired - Lifetime USRE41315E1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9904723A SE9904723D0 (sv) 1999-12-22 1999-12-22 New modulators of dopamine neurotransmission II
SE9904723 1999-12-22
PCT/SE2000/002675 WO2001046146A1 (en) 1999-12-22 2000-12-22 New modulators of dopamine neurotransmission

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US10/168,019 Reissue US6924374B2 (en) 1999-12-22 2000-12-22 Modulators of dopamine neurotransmission

Publications (1)

Publication Number Publication Date
USRE41315E1 true USRE41315E1 (en) 2010-05-04

Family

ID=20418252

Family Applications (2)

Application Number Title Priority Date Filing Date
US11/904,013 Expired - Lifetime USRE41315E1 (en) 1999-12-22 2000-12-22 Modulators of dopamine neurotransmission
US10/168,019 Ceased US6924374B2 (en) 1999-12-22 2000-12-22 Modulators of dopamine neurotransmission

Family Applications After (1)

Application Number Title Priority Date Filing Date
US10/168,019 Ceased US6924374B2 (en) 1999-12-22 2000-12-22 Modulators of dopamine neurotransmission

Country Status (30)

Country Link
US (2) USRE41315E1 (pt)
EP (2) EP1419773B1 (pt)
JP (1) JP5096654B2 (pt)
KR (1) KR100771287B1 (pt)
CN (1) CN1196680C (pt)
AT (1) ATE397446T1 (pt)
AU (1) AU778183B2 (pt)
BG (1) BG65698B1 (pt)
BR (1) BR0016635A (pt)
CA (1) CA2394606C (pt)
CZ (1) CZ302907B6 (pt)
DE (1) DE60039131D1 (pt)
DK (1) DK1419773T3 (pt)
EE (1) EE05083B1 (pt)
ES (1) ES2307861T3 (pt)
HK (1) HK1054228B (pt)
HR (1) HRP20020539B1 (pt)
HU (1) HUP0203874A3 (pt)
IL (2) IL150350A0 (pt)
MX (1) MXPA02006317A (pt)
NO (1) NO323329B1 (pt)
NZ (2) NZ519566A (pt)
PL (1) PL205092B1 (pt)
PT (1) PT1419773E (pt)
RU (1) RU2262504C2 (pt)
SE (1) SE9904723D0 (pt)
SK (1) SK287366B6 (pt)
UA (1) UA73337C2 (pt)
WO (1) WO2001046146A1 (pt)
ZA (1) ZA200204813B (pt)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080234321A1 (en) * 2005-10-13 2008-09-25 Clas Sonesson 3,5-Disubstituted Phenyl-Piperidines as Modulators of Dopamine Neurotransmission
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9904724D0 (sv) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission I
SE9904723D0 (sv) 1999-12-22 1999-12-22 Carlsson A Research Ab New modulators of dopamine neurotransmission II
US20070021404A1 (en) * 2003-06-24 2007-01-25 Dan Peters Novel aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
DE10361259A1 (de) * 2003-12-24 2005-07-28 Schwarz Pharma Ag Verwendung von Rotigotine in einem Frühstadium von Morbus Parkinson zur Prävention des weiteren Neuronenverlustes
JP2008501748A (ja) * 2004-06-08 2008-01-24 ニューロサーチ スウェーデン アクチボラゲット ドーパミン神経伝達のモジュレーターとしての新規な置換されたピペリジン
DE602005021641D1 (de) 2004-06-08 2010-07-15 Nsab, Filial Af Neurosearch Sweden Ab Neue disubstituierte phenylpiperidine und piperazine als modulatoren der dopamin-neurotransmission
US7851629B2 (en) 2004-06-08 2010-12-14 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
SE0401464D0 (sv) * 2004-06-08 2004-06-08 Carlsson A Research Ab New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
SE0401465D0 (sv) 2004-06-08 2004-06-08 Carlsson A Research Ab New substituted piperdines as modulators of dopamine neurotransmission
AU2005251906B2 (en) 2004-06-08 2011-03-31 Nsab, Filial Af Neurosearch Sweden Ab, Sverige New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
RU2006140687A (ru) * 2004-06-18 2008-07-27 Ньюросерч А/С (DK) Новые алкил-замещенные производные пиперазина и их применение в качестве ингибиторов обратного захвата моноаминовых нейротрансмиттеров
JP2008515952A (ja) * 2004-10-13 2008-05-15 ニューロサーチ スウェーデン アクチボラゲット ４−（３−スルホニルフェニル）−ピペリジンの合成方法
WO2006040155A1 (en) 2004-10-13 2006-04-20 Neurosearch Sweden Ab Process for the synthesis of 4-(3-methanesulfonylphenyl)-1-n-propyl-piperidine
ITMI20051193A1 (it) * 2005-06-24 2006-12-25 Acraf Uso farmaceutico di una 1-3-clorofenil-3-alchilpiperazina
JP2009518337A (ja) 2005-12-07 2009-05-07 エヌエスエイビー、フィリアル アヴ ノイロサーチ スウェーデン エービー、スヴェーリエ 皮質カテコールアミン作動性神経伝達のモジュレーターとしての二置換フェニルピペリジン
RU2470013C2 (ru) * 2007-04-12 2012-12-20 НСАБ, Филиаль ау НьюроСёрч Свиден АБ, Сверийе N-оксидные и/или ди-n-оксидные производные стабилизаторов/модуляторов рецепторов дофамина, проявляющие улучшенные профили сердечно-сосудистых побочных эффектов
CN101711234A (zh) 2007-06-05 2010-05-19 Nsab神经研究瑞典公司分公司 作为皮层儿茶酚胺能神经传递调节剂的新型二取代的苯基吡咯烷
EP2155671B8 (en) 2007-06-05 2018-02-21 Integrative Research Laboratories Sweden AB Disubstituted phenylpyrrolidines as modulators of cortical catecholaminergic neurotransmission
NZ588209A (en) * 2008-04-29 2012-08-31 Nsab Af Neurosearch Sweden Ab 1-(2,3-dihydro-1,4-benzodioxin-2-yl)-methanamine derivatives for the modulation of dopaminergic function in the central nervous system
WO2009133109A1 (en) * 2008-04-29 2009-11-05 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Modulators of dopamine neurotransmission
WO2009133110A1 (en) * 2008-04-29 2009-11-05 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Modulators of dopamine neurotransmission
WO2011107583A1 (en) 2010-03-04 2011-09-09 Nsab, Filial Af Neurosearch Sweden Ab, Sverige Substituted 4-phenyl-n-alkyl-piperidines for preventing onset or slowing progression of neurodegenerative disorders
SG188298A1 (en) 2010-09-03 2013-04-30 Ivax Int Gmbh Deuterated analogs of pridopidine useful as dopaminergic stabilizers
WO2013034622A1 (en) 2011-09-07 2013-03-14 Neurosearch A/S Polymorphic form of pridopidine hydrochloride
MX347209B (es) 2011-12-08 2017-04-19 Teva Pharmaceuticals Int Gmbh La sal de bromhidrato de pridopidina.
MX2014011971A (es) 2012-04-04 2015-01-16 Ivax Int Gmbh Composiciones farmaceuticas para terapia de combinacion.
AR105434A1 (es) 2015-07-22 2017-10-04 Teva Pharmaceuticals Int Gmbh Proceso para preparar pridopidina

Citations (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB850662A (en) 1956-10-22 1960-10-05 Parke Davis & Co Substituted piperazines and processes for their production
NL6510107A (pt) 1964-08-05 1966-02-07
US3326916A (en) 1964-04-14 1967-06-20 May & Baker Ltd N-phenylpiperazine compounds
US3539573A (en) 1967-03-22 1970-11-10 Jean Schmutz 11-basic substituted dibenzodiazepines and dibenzothiazepines
GB1560271A (en) 1977-01-14 1980-02-06 Joullie International Sa Therapeutically useful m-trifluoromethylphenylpiperazine derivatives
GB2027703A (en) 1978-08-01 1980-02-27 Synthelabo 1-Phenylpiperazine derivatives
US4202898A (en) 1978-06-05 1980-05-13 Synthelabo Method of treating anxiety and depression
US4267328A (en) 1978-08-01 1981-05-12 Synthelabo 1-Phenylpiperazines
GB2078746A (en) 1980-06-30 1982-01-13 Taiho Pharmaceutical Co Ltd Piperazine derivatives for use as analgesics
GB2083476A (en) 1980-09-12 1982-03-24 Wyeth John & Brother Ltd Heterocyclic compounds
US4333942A (en) 1979-08-03 1982-06-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Anti-depressant and analgesic 4-phenoxypiperidines
EP0060179A1 (fr) 1981-03-11 1982-09-15 Sanofi S.A. Compositions pharmaceutiques à action anorexigène
US4415736A (en) 1981-12-28 1983-11-15 E. I. Du Pont De Nemours & Co. Certain tetrahydropyridine intermediates
EP0094159A1 (en) 1982-05-10 1983-11-16 Takeda Chemical Industries, Ltd. Dihydropyridine derivatives, their production and use
US4504660A (en) 1982-07-06 1985-03-12 American Home Products Corporation Process for the production of 2,6-diaminobenzonitrile derivatives
WO1989005799A1 (en) 1987-12-14 1989-06-29 Richter Gedeon Vegyészeti Gyár RT Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same
US4892975A (en) 1987-09-28 1990-01-09 President And Fellows Of Harvard College Diethynyl monomers and polymers thereof
EP0369887A2 (fr) 1988-11-18 1990-05-23 Sanofi Utilisation de trifluorométhylphényltétrahydropyridines pour la préparation de médicaments destinés à combattre les troubles anxio-dépressifs
WO1991009594A1 (en) 1989-12-28 1991-07-11 Virginia Commonwealth University Sigma receptor ligands and the use thereof
WO1992018475A2 (en) 1991-04-17 1992-10-29 The Upjohn Company Substituted phenylazacycloalkanes as cns agents
WO1993000313A2 (en) 1991-06-27 1993-01-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof
WO1993004684A1 (en) 1991-09-11 1993-03-18 Mcneilab, Inc. Novel 4-arylpiperazines and 4-arylpiperidines
EP0533267A1 (en) 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533268A1 (en) 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533266A1 (en) 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0659743A1 (en) 1993-12-27 1995-06-28 Hoechst Aktiengesellschaft Piperidine derivatives as inhibitors of platelet aggregation and their preparation
EP0675118A2 (en) 1994-03-29 1995-10-04 Eisai Co., Ltd. Biphenylderivatives, process for their preparation and their use as medicaments
US5502050A (en) 1993-11-29 1996-03-26 Cornell Research Foundation, Inc. Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis
WO1997003986A1 (fr) 1995-07-19 1997-02-06 Yoshitomi Pharmaceutical Industries, Ltd. Composes fusionnes de triazole
WO1998011068A1 (de) 1996-09-13 1998-03-19 Merck Patent Gmbh Piperazin-derivate mit einer selektivität für den d-4 rezeptor
WO2000003713A1 (en) 1998-07-14 2000-01-27 Nelson Jodi A Treatment for schizophrenia and other dopamine system dysfunctions
JP2000086603A (ja) 1998-07-15 2000-03-28 Yoshitomi Pharmaceut Ind Ltd 桂皮酸アミド誘導体および３―フェニルプロピオン酸アミド誘導体
WO2000078728A1 (en) 1999-06-22 2000-12-28 Neurosearch A/S Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
US6175015B1 (en) 1996-08-12 2001-01-16 Neurogen Corporation Fused indolecarboxamides: dopamine receptor subtype specific ligands
WO2001046145A1 (en) 1999-12-22 2001-06-28 A. Carlsson Research Ab New modulators of dopamine neurotransmission
WO2002005819A1 (en) 2000-07-15 2002-01-24 Smithkline Beecham Corporation Compounds and methods
WO2002059108A1 (en) 2001-01-23 2002-08-01 Eli Lilly And Company Melanocortin receptor agonists
EP1419773A2 (en) 1999-12-22 2004-05-19 A. Carlsson Research AB 4-Phenylpiperidine derivatives as modulators of dopamine neurotransmission
WO2004099150A2 (en) 2003-04-30 2004-11-18 Wyeth 3-(1-naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands
WO2005019215A1 (en) 2003-08-22 2005-03-03 Warner-Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
US6906120B1 (en) 2000-06-20 2005-06-14 General Electric Poly(arylene ether) adhesive compositions
WO2005121087A1 (en) 2004-06-08 2005-12-22 A. Carlsson Research Ab New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
WO2005121092A1 (en) 2004-06-08 2005-12-22 A. Carlsson Research Ab New substituted piperidines as modulators of dopamine neurotransmission
WO2007042295A1 (en) 2005-10-13 2007-04-19 Neurosearch Sweden Ab 3, 5-disubstituted phenyl-piperidines as mdulators of dopamine? neurotransmission
WO2007065655A1 (en) 2005-12-07 2007-06-14 Neurosearch Sweden Ab Disubstituted phenylpiperidines as modulators of cortical catecholaminergic neurotransmission
US20070149542A1 (en) 2004-06-08 2007-06-28 Clas Sonesson Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
US20070179185A1 (en) 2004-06-08 2007-08-02 Clas Sonesson New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2027703A (en) * 1934-06-21 1936-01-14 Ribar Peter Shoe jack
DE1019308B (de) * 1954-07-19 1957-11-14 Hoechst Ag Verfahren zur Herstellung gegen Bilharzia-Infektionen wirksamer 4-Phenyl-piperazine
NL6607959A (pt) * 1965-06-10 1966-12-12
CA1061356A (en) * 1975-10-03 1979-08-28 Dieter H. Klaubert 2-cyano-3- or 4-(substituted amino) oxanilic acid derivatives
JPS5714585A (en) * 1980-06-30 1982-01-25 Taiho Yakuhin Kogyo Kk 1-cycloalkylmethylpiperazine derivative
JPS5815979A (ja) * 1981-07-11 1983-01-29 Kyowa Hakko Kogyo Co Ltd 新規なピペリジン誘導体およびその製造法
ES8602674A1 (es) * 1985-02-07 1985-12-01 Inst Investigacion Desarrollo Un nuevo procedimiento de obtencion de derivados del acido quinolincarboxilico
TW240217B (pt) * 1992-12-30 1995-02-11 Glaxo Group Ltd
GB2276160A (en) * 1993-03-17 1994-09-21 Glaxo Group Ltd Ethanone compounds.
US5571822A (en) * 1994-09-30 1996-11-05 The University Of North Carolina At Chapel Hill Antitumor compounds
FR2740134B1 (fr) * 1995-10-18 1998-01-09 Pf Medicament Derives d'amines cycliques d'aryl-piperazines, leur preparation et les compositions pharmaceutiques les contenant
DZ2376A1 (fr) * 1996-12-19 2002-12-28 Smithkline Beecham Plc Dérivés de sulfonamides nouveaux procédé pour leurpréparation et compositions pharmaceutiques les c ontenant.
US6663587B2 (en) * 2001-06-22 2003-12-16 Medela Holding Ag Breastshield with multi-pressure and expansible chamber construction, related breastpump and method

Patent Citations (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB850662A (en) 1956-10-22 1960-10-05 Parke Davis & Co Substituted piperazines and processes for their production
US3326916A (en) 1964-04-14 1967-06-20 May & Baker Ltd N-phenylpiperazine compounds
NL6510107A (pt) 1964-08-05 1966-02-07
GB1060160A (en) 1964-08-05 1967-03-01 Allen & Hanburys Ltd 4-phenylpiperidine derivatives
US3458521A (en) 1964-08-05 1969-07-29 Allen & Hanburys Ltd 4-phenylpiperidine derivatives
US3539573A (en) 1967-03-22 1970-11-10 Jean Schmutz 11-basic substituted dibenzodiazepines and dibenzothiazepines
GB1560271A (en) 1977-01-14 1980-02-06 Joullie International Sa Therapeutically useful m-trifluoromethylphenylpiperazine derivatives
US4203986A (en) 1977-01-14 1980-05-20 Metabio-Joullie M-Trifluoro-methylphenyl-piperazine
US4202898A (en) 1978-06-05 1980-05-13 Synthelabo Method of treating anxiety and depression
GB2027703A (en) 1978-08-01 1980-02-27 Synthelabo 1-Phenylpiperazine derivatives
US4267328A (en) 1978-08-01 1981-05-12 Synthelabo 1-Phenylpiperazines
US4333942A (en) 1979-08-03 1982-06-08 Byk Gulden Lomberg Chemische Fabrik Gmbh Anti-depressant and analgesic 4-phenoxypiperidines
GB2078746A (en) 1980-06-30 1982-01-13 Taiho Pharmaceutical Co Ltd Piperazine derivatives for use as analgesics
GB2083476A (en) 1980-09-12 1982-03-24 Wyeth John & Brother Ltd Heterocyclic compounds
EP0060179A1 (fr) 1981-03-11 1982-09-15 Sanofi S.A. Compositions pharmaceutiques à action anorexigène
US4415736A (en) 1981-12-28 1983-11-15 E. I. Du Pont De Nemours & Co. Certain tetrahydropyridine intermediates
EP0094159A1 (en) 1982-05-10 1983-11-16 Takeda Chemical Industries, Ltd. Dihydropyridine derivatives, their production and use
US4892875A (en) 1982-05-10 1990-01-09 Takeda Chemical Industries, Ltd. Substituted heterocyclylalkyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acids
US4504660A (en) 1982-07-06 1985-03-12 American Home Products Corporation Process for the production of 2,6-diaminobenzonitrile derivatives
US4892975A (en) 1987-09-28 1990-01-09 President And Fellows Of Harvard College Diethynyl monomers and polymers thereof
WO1989005799A1 (en) 1987-12-14 1989-06-29 Richter Gedeon Vegyészeti Gyár RT Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same
EP0369887A2 (fr) 1988-11-18 1990-05-23 Sanofi Utilisation de trifluorométhylphényltétrahydropyridines pour la préparation de médicaments destinés à combattre les troubles anxio-dépressifs
US5026716A (en) 1988-11-18 1991-06-25 Sanofi Method of treatment of anxiety and anxio-depressive disorders
WO1991009594A1 (en) 1989-12-28 1991-07-11 Virginia Commonwealth University Sigma receptor ligands and the use thereof
WO1992018475A2 (en) 1991-04-17 1992-10-29 The Upjohn Company Substituted phenylazacycloalkanes as cns agents
US5462947A (en) 1991-04-17 1995-10-31 The Upjohn Company Centrally acting substituted phenylazacycloalkanes
WO1993000313A2 (en) 1991-06-27 1993-01-07 Virginia Commonwealth University Sigma receptor ligands and the use thereof
WO1993004684A1 (en) 1991-09-11 1993-03-18 Mcneilab, Inc. Novel 4-arylpiperazines and 4-arylpiperidines
EP0533267A1 (en) 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533268A1 (en) 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
EP0533266A1 (en) 1991-09-18 1993-03-24 Glaxo Group Limited Benzanilide derivatives as 5-HT1D antagonists
US5502050A (en) 1993-11-29 1996-03-26 Cornell Research Foundation, Inc. Blocking utilization of tetrahydrobiopterin to block induction of nitric oxide synthesis
EP0659743A1 (en) 1993-12-27 1995-06-28 Hoechst Aktiengesellschaft Piperidine derivatives as inhibitors of platelet aggregation and their preparation
CN1117966A (zh) 1994-03-29 1996-03-06 卫材株式会社 联苯基衍生物
EP0675118A2 (en) 1994-03-29 1995-10-04 Eisai Co., Ltd. Biphenylderivatives, process for their preparation and their use as medicaments
WO1997003986A1 (fr) 1995-07-19 1997-02-06 Yoshitomi Pharmaceutical Industries, Ltd. Composes fusionnes de triazole
US6175015B1 (en) 1996-08-12 2001-01-16 Neurogen Corporation Fused indolecarboxamides: dopamine receptor subtype specific ligands
WO1998011068A1 (de) 1996-09-13 1998-03-19 Merck Patent Gmbh Piperazin-derivate mit einer selektivität für den d-4 rezeptor
CN1230180A (zh) 1996-09-13 1999-09-29 默克专利股份有限公司 具有d4受体选择性的哌嗪衍生物
WO2000003713A1 (en) 1998-07-14 2000-01-27 Nelson Jodi A Treatment for schizophrenia and other dopamine system dysfunctions
JP2000086603A (ja) 1998-07-15 2000-03-28 Yoshitomi Pharmaceut Ind Ltd 桂皮酸アミド誘導体および３―フェニルプロピオン酸アミド誘導体
WO2000078728A1 (en) 1999-06-22 2000-12-28 Neurosearch A/S Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
EP1240142A1 (en) 1999-12-22 2002-09-18 A. Carlsson Research AB New modulators of dopamine neurotransmission
US6903120B2 (en) 1999-12-22 2005-06-07 A. Carlsson Research Ab Modulators of dopamine neurotransmission
US7417043B2 (en) 1999-12-22 2008-08-26 Neurosearch Sweden Ab Modulators of dopamine neurotransmission
US6924374B2 (en) 1999-12-22 2005-08-02 A. Carlsson Research Ab Modulators of dopamine neurotransmission
EP1240141A1 (en) 1999-12-22 2002-09-18 A. Carlsson Research AB New modulators of dopamine neurotransmission
WO2001046145A1 (en) 1999-12-22 2001-06-28 A. Carlsson Research Ab New modulators of dopamine neurotransmission
EP1419773A2 (en) 1999-12-22 2004-05-19 A. Carlsson Research AB 4-Phenylpiperidine derivatives as modulators of dopamine neurotransmission
WO2001046144A1 (en) 1999-12-22 2001-06-28 A. Carlsson Research Ab New modulators of dopamine neurotransmission
US6906120B1 (en) 2000-06-20 2005-06-14 General Electric Poly(arylene ether) adhesive compositions
WO2002005819A1 (en) 2000-07-15 2002-01-24 Smithkline Beecham Corporation Compounds and methods
WO2002059108A1 (en) 2001-01-23 2002-08-01 Eli Lilly And Company Melanocortin receptor agonists
WO2004099150A2 (en) 2003-04-30 2004-11-18 Wyeth 3-(1-naphthyl)-2-cyanopropanoic acid derivatives as estrogen receptor ligands
WO2005019215A1 (en) 2003-08-22 2005-03-03 Warner-Lambert Company Llc [1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia
WO2005121087A1 (en) 2004-06-08 2005-12-22 A. Carlsson Research Ab New disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
WO2005121092A1 (en) 2004-06-08 2005-12-22 A. Carlsson Research Ab New substituted piperidines as modulators of dopamine neurotransmission
WO2005121088A1 (en) 2004-06-08 2005-12-22 A. Carlsson Research Ab New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
US20070149542A1 (en) 2004-06-08 2007-06-28 Clas Sonesson Disubstituted phenylpiperidines/piperazines as modulators of dopamine neurotransmission
US20070179185A1 (en) 2004-06-08 2007-08-02 Clas Sonesson New disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission
WO2007042295A1 (en) 2005-10-13 2007-04-19 Neurosearch Sweden Ab 3, 5-disubstituted phenyl-piperidines as mdulators of dopamine? neurotransmission
WO2007065655A1 (en) 2005-12-07 2007-06-14 Neurosearch Sweden Ab Disubstituted phenylpiperidines as modulators of cortical catecholaminergic neurotransmission

Non-Patent Citations (42)

* Cited by examiner, † Cited by third party
Title
Bloom et al. (Editors), Psychopharmacology-The Fourth Generation of Progress, Chapter 21, pp. 227, 237; Chapter 22, pp. 245, 254; Chapter 25, pp. 283, 292; Chapter 26, pp. 295-301; Chapter 66, pp. 759-760, 1725, 744-746; Chapter 68, pp. 787, 793-795; Chapter 80, pp. 921-925, 927-028; Chapter 101, pp. 1205, 1207-1209; Chapter 111, pp. 1311, 1317, 1318, 1320; Chapter 126, pp. 1479-1482; Chapter 137, pp. 1591, 1600; Chapter 138, pp. 1609-1610, 1612 (1995) Raven Press, New York, New York, USA.
Bradbury et al., "Biochemical Changes Caused by the Infusion Into the Substantia Nigra of the Rat of MPTP and Related Compounds Which Antagonise Dihydropteridine Reductase", Neuropharmacology, vol. 25, No. 6, pp. 583-586, 1986.
Carlsson et al., Interactions Between Glutamatergic and Monoaminergic Systems within the Basal Ganglia-Implications for Schizophrenia and Parkinson's Disease, TINS (1990), pp. 272-276, vol. 13, No. 7, Elsevier Science Publishers Ltd., United Kingdom.
Chemical Abstract CA 106:138355, Reaction of spiro[4H-3, 1-benzoxazine-4-4′-piperidin]-2(1H)-one derivatives and related compounds with phosphorus oxychloride, Takai, et al., Chemical & Pharmaceutical Bulletin (1986), 34(5), 1901-6.
Chemical Abstract CA 106:138355, Reaction of spiro[4H-3, 1-benzoxazine-4-4'-piperidin]-2(1H)-one derivatives and related compounds with phosphorus oxychloride, Takai, et al., Chemical & Pharmaceutical Bulletin (1986), 34(5), 1901-6.
Chemical Abstract CA 107:39724, Pyridonecarboxylic acids as antibacterial agents. Part 6. A new synthesis of 7H-pyrido [1,2,3-de][1,4]benzoxazine derivatives including an antibacterial agent, ofloxacin, Egawa, et al., Chemical & Pharmaceutical Bulletin (1986), 34(10), 4098-102.
Chemical Abstract CA 116:250000, Quantitative structure-metabolism relationship analyses of MAO-mediated toxication of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analogs, Altomare, et al., Chemical Research in Toxicology (1992), 5(3), 366-75.
Chemical Abstract CA 123:143666, Synthesis of 5-and 6-membered heterocycles by a strategy combining SNAr and SRN1 reactions, Beugelmans, et al., Bulletin de la Societe Chimique de France (1995), 132(3), 306-13.
Chemical Abstract CA 128:321617, Practical application of the palladium-catalyzed amination in phenylpiperazine synthesis: an efficient synthesis of a metabolite of the antipsychotic agent aripiprazole, Morita, et al., Tetrahedron (1998), 54(19), 4811-4818.
Chemical Abstract CA 129:49313, Mono-and difunctional nitrogen mustard analogs of the DNA minor groove binder pibenzimol. Synthesis, cytotoxicity and interaction with DNA, Smaill, et al., Anti-Cancer Drug Design (1998) 13(3), 221-242.
Chemical Abstract CA 132:35590, Synthesis of piperidine analogs of 1-(3-chloropheynl)piperazine, a well known serotonin ligand, Radl, et al., Journal of Heterocyclic Chemistry (1999), 36(4). 1017-1022.
Chemical Abstract CA 66:37889, A facile synthesis of piperazines from primary amines, Henry, Journal of Heterocyclic Chemistry (1966), 3(4), 503-11.
Chemical Abstract CA 71:29130, Comparison of Schistosomicidal activity of xanthenones and 4-methyl-3-chloroanilines and their hydroxymethyl analogs in Swiss mice and Syrian hamsters infected with Schistosma mansoni, Berberian et al., Journal of Medicinal Chemistry (1969), 12(4), 607-10.
Chemical Abstract CA 77:122113, Antimalarial drugs. 25. Folate antagonists. 3. 2,4-Diamino-6-(heterocyclic)quinazolines, a novel class of antimetabolites with potent antimalarial and antibacterial activity, Elslager, et al., Journal of Medicinal Chemistry (1972), 15(8), 827-36.
Chemical Abstract CA 93:94913, Cine and tele substitutions in the reaction of 2,3-dinitroaniline with secondary amines, Self, et al., Journal of the Chemical Society, Chemical Communications (1980), (6), 281-2.
Chemical Abstract CA 95:237, N-(Aminophenyl)oxamic acids and esters as potent, orally active antiallergy agents, Klaubert, et al., Journal of Medicinal Chemistry (1981) 24(6), 742-8.
Chemical Abstract CA 97:109953, Studies on antimalarials. III. Synthesis and antimalarial effects of some derivatives of 2,4-diamino-6-substituted piperazinylquinazolines, Zhang, et al., Yaoxue Xuebao (1981), 16(6), 415-24.
Coyle, et al., Alzheimer's Disease: A Disorder of Cortical Cholinergic Innvervation, Science, vol. 219, Mar. 1983, pp. 1184-1190.
English translation of Jul. 12, 2006, Korean Official Action issued in counterpart Korean Application No. 2005-7024520 corresponding to U.S. Appl. No. 11/016,967.
Examiner's first report dated Feb. 3, 2003, on Australian patent application No. 25705/01 corresponding to USPN 6,906,120.
Examiner's first report dated Feb. 3, 2003, on Australian patent application No. 25705/01 corresponding to USPN 6,924,374.
Feldman, et al., Principles of Neuropsychopharmacology, Chapter 17-Mind Altering Drugs, (1997), pp. 731, 762-763, Sinauer Associates, Inc., Publishers, Sunderland, Massachussetts, USA.
Gessner et al., Synthesis and Dihydropteridine Reductase Inhibitory Effects of Potential Metabolites of the Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Journal of Medicinal Chemistry, American Chemical Society, vol. 28, No. 3, 1985, pp. 311-317.
Grunblatt et al., "Neuroprotective Strategies in Parkinson's Disease Using the Models of 6-Hydroxydopamine and MPTP", Ann NY Acad. Sci., vol. 899, pp. 262-273, 2000.
Grunblatt et al., "Potent Neuroprotective and Antioxidant Activity of Apomorphine in MPTP and 6-Hydroxydopamine Induced Neurotoxicity", J. Neural Transm. Suppl., vol. 55, pp. 57-70, 1999.
Hansch et al., "A Survey of Hammett Substituent Constants and Resonance and Field Parameters", Chem. Rev., vol. 91, pp. 165-195, 1991.
International Search Report and International Preliminary Examination Report dated Aug. 6, 2001, issued in PCT/SE00/02674 which is counterpart to USPN 6,903,120.
International Search Report and International Preliminary Examination Report dated Aug. 6, 2001, issued in PCT/SE00/02675 which is counterpart to USPN 6,924,374.
International Search Report and International Preliminary Examination Report dated Oct. 29, 2001, issued in PCT/SE00/02673 which is counterpart to U.S. Appl. No. 10/168,297.
International Search Report dated Oct. 18, 2005, issued in PCT Application No. PCT/EP2005/006147.
Journal Chem. Society, Bergel et al., 1944, pp. 261-264, Beiltsein Registry No. 183878 and 206256, Bielstein Institute for Organic Chemistry, Frankfurt-Main, Germany.
Manoury, et al., "Synthesis and Analgesic Activities of Some (4-Substituted phenyl-1-piperazinyl)alkyl 2-Aminobenzoates and 2-Aminocotinates", Journal of Medicinal Chemistry, 1979, pp. 554-559, vol. 22, No. 5, Amerian Chemical Society, Washington, DC.
Mar. 19, 2004, office action in Chinese application No. 00818258.2 which is counterpart to USPN 6,924,374, and instructions for response.
Morita, et al., "Practical Application of the Palladium-catalyzed Amination in Phenylpiperazine Synthesis: An Efficient Synthesis of a Metabolite of the Antipsychotic Agent Aripiprazole", Tetrahedron, May 7, 1998, pp. 4811-4818, vol. 54, No. 19, Pergamon, Elsevier Science Ltd., Oxford, England & NY, USA.
Nacci et al., "Richerche Su Sostanze Ad Attivita Antiblastica", Farmaco-Ed. Sc., vol. 28, Fasc. 5, pp. 399-410, 2007.
Oshiro, et al., "Novel Antisychotic Agents with Dopamine Autoreceptor Agonist Properties: Synthesis and Pharmacology of 7-[4-Phenyl-1-piperazinyl)butoxyl]-3,4-dihydro-2(1H)-quinolinone Derivatives", J. Med.Chem., 1998, pp. 658-667, vol. 41, American Chemical Society, Washington, DC.
Patent Family Reference to U.S. Pat. No. 1,459,013 and English Abstracts.
Patent Family Reference to WO 1997/003986 and English Abstracts.
Sonesson, et al., Substituted (S)-Phenylpiperidines and Rigid Congeners as Preferential Dopamine Autoreceptor Antagonists: Synthesis and Structure-Activity Relationships, Journal of Medicinal Chemistry (1994), 37, pp. 2735-2753.
Strange, Philip G., Antipsychotic Drugs: Importance of Dopamine Receptors for Mechanisms of Therapeutic Actions and Side Effects, Pharmacol Rev 53:119-133, (2001), vol. 53, No. 1.
V. Nacci, et al., Antiblastic Substances. Lil. Tylophorine Analogs. 1. Synthesis and Cytostotic and Cytoxic Activity of 4-(3,4-dimethoxyphenyl)piperidine, Farmaco, Edizione Scientifica, vol. 328, No. 5, 1973, pp. 399-410.
Wolff, Manfred E., Burger's Medicinal Chemistry-4th Edition, Part III, John Wiley & Sons, 1979, pp. 872-873.

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE46117E1 (en) 1999-12-22 2016-08-23 Teva Pharmaceuticals International Gmbh Modulators of dopamine neurotransmission
US20080234321A1 (en) * 2005-10-13 2008-09-25 Clas Sonesson 3,5-Disubstituted Phenyl-Piperidines as Modulators of Dopamine Neurotransmission
US8501777B2 (en) * 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission

Also Published As

Publication number Publication date
CZ302907B6 (cs) 2012-01-18
ATE397446T1 (de) 2008-06-15
NZ519566A (en) 2004-05-28
NO20022879L (no) 2002-08-21
IL150350A0 (en) 2002-12-01
ES2307861T3 (es) 2008-12-01
CA2394606A1 (en) 2001-06-28
BG65698B1 (bg) 2009-07-31
BR0016635A (pt) 2002-10-15
US6924374B2 (en) 2005-08-02
CN1196680C (zh) 2005-04-13
SK8662002A3 (en) 2003-02-04
SE9904723D0 (sv) 1999-12-22
CA2394606C (en) 2009-06-02
AU778183B2 (en) 2004-11-18
HRP20020539B1 (en) 2009-06-30
EE05083B1 (et) 2008-10-15
RU2262504C2 (ru) 2005-10-20
KR20020067565A (ko) 2002-08-22
DK1419773T3 (da) 2008-09-22
MXPA02006317A (es) 2004-05-14
DE60039131D1 (de) 2008-07-17
ZA200204813B (en) 2003-08-27
NO20022879D0 (no) 2002-06-17
SK287366B6 (sk) 2010-08-09
BG106845A (en) 2003-04-30
EP1240143A1 (en) 2002-09-18
CZ20022074A3 (cs) 2002-10-16
IL150350A (en) 2010-05-31
AU2570601A (en) 2001-07-03
KR100771287B1 (ko) 2007-10-29
HUP0203874A2 (hu) 2003-03-28
EP1419773A2 (en) 2004-05-19
EP1419773A3 (en) 2004-05-26
NO323329B1 (no) 2007-03-26
HUP0203874A3 (en) 2005-03-29
JP2003518096A (ja) 2003-06-03
JP5096654B2 (ja) 2012-12-12
NZ531643A (en) 2005-03-24
HRP20020539A2 (en) 2004-08-31
PL362251A1 (en) 2004-10-18
RU2002119417A (ru) 2004-01-10
CN1420870A (zh) 2003-05-28
EP1419773B1 (en) 2008-06-04
HK1054228A1 (en) 2003-11-21
US20030004169A1 (en) 2003-01-02
PL205092B1 (pl) 2010-03-31
HK1054228B (zh) 2005-09-16
UA73337C2 (en) 2005-07-15
PT1419773E (pt) 2008-07-01
WO2001046146A1 (en) 2001-06-28
EE200200345A (et) 2003-06-16

Similar Documents

Publication Publication Date Title
USRE41315E1 (en) Modulators of dopamine neurotransmission
US6903120B2 (en) Modulators of dopamine neurotransmission
USRE46117E1 (en) Modulators of dopamine neurotransmission
AU2005200729B2 (en) New modulators of dopamine neurotransmission

Legal Events

Date Code Title Description
AS Assignment

Owner name: NEUROSEARCH SWEDEN AB,SWEDEN

Free format text: CHANGE OF NAME;ASSIGNOR:A CARLSSON RESEARCH AB;REEL/FRAME:019951/0099

Effective date: 20061213

AS Assignment

Owner name: NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE,DEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NEUROSEARCH SWEDEN AB;REEL/FRAME:021869/0379

Effective date: 20080630

CC Certificate of correction
FEPP Fee payment procedure

Free format text: PAT HOLDER CLAIMS SMALL ENTITY STATUS, ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: LTOS); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

FPAY Fee payment

Year of fee payment: 8

AS Assignment

Owner name: SANIONA AB, DENMARK

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NSAB, FILIAL AF NEUROSEARCH SWEDEN AB, SVERIGE;REEL/FRAME:039472/0179

Effective date: 20160817

FPAY Fee payment

Year of fee payment: 12